THE ROLE OF NITRIC-OXIDE IN HEMODYNAMIC AND METABOLIC ALTERATIONS INDUCED BY PROSTAGLANDIN-F2-ALPHA IN THE PERFUSED-RAT-LIVER

In the liver prostaglandins have been shown to be potent regulators of portal blood flow, carbohydrate metabolism and bile secretion. It is not known whether these effects represent a direct action of prostagla ndins, and it has been suggested that nitric oxide (NO) might be a cri tical mediator for prostaglandin induced hepatic events. We have studi ed whether nitric oxide formation or inhibition alters the action of p rostaglandin F-2 alpha (PG F-2 alpha) in a single-pass liver perfusion model. The liver of untreated rats (constitutive NO-synthase) or afte r pretreatment with endotoxin (inducible form of NO-synthase) was perf used at a constant pressure via the portal vein. Effluate were collect ed in I-min intervals and bile in 5-min intervals. In both groups the addition of PG F-2 alpha (10 mu M) to the perfusate for 5 min resulted in a significant increase of glucose and lactate production, and in a significant decrease in portal blood flow (-0.56+/-0.04 ml/g per min) , in bile flow (-60.7%) and in bile acid release (-60.6%). Inhibition of NO synthase by adding N-G-monomethyl-L-arginine (L-NMMA, 100 mu M) to the perfusate did not affect any of the alterations induced by PG F -2 alpha. Substitution of the endogenous substrate for the NO synthase L-arginine (500 mu M) in the perfusate completely prevented the hemod ynamic alterations induced by PG F-2 alpha in endotoxin pretreated liv ers and limited the flow reduction (0.15+/-0.04 ml/g per min) in the u ntreated group. The substitution of L-arginine in the perfusate of end otoxin pretreated livers raised nitrite (from 1.5+/-0.3 to 3.6+/-0.7 n mol/g per min) and urea release (from 65+/-25 to 294+/-68 nmol/g per m in), but had no effect on any of the other metabolic parameters and bi le secretion. We conclude that PG F-2 alpha increases glucose and lact ate production in the perfused rat liver and decreases portal flow and bile secretion. The metabolic effects induced by PG F-2 alpha appear to be independent of NO mediation and hemodynamic alterations. Portal flow alone can be influenced by endogenous NO formation.